It is proposed to synthesize 2'-0-alkyl (methyl, ethyl and propargyl)-thiophosphonate-ribo Oligonucleotides (fig. 5,6,7) and their precursors, viz; 2'-0-alkyl (methyl, ethyl, and propargyl)-N-protected-5'-DMT-3'-H-Phosphonates (fig. 9,12,13). Solid phase Oligonucleotide synthesis would be optimized to produce model oligomers of the chain-length 18-20 nucleotide long in the class of structures, 5,6,7,. These structures would be extremely valuable therapeutics prototypes to establish their inhibitory potency as antisense oligonucleotides. They are expected to hybridize to target DNA or RNA sequences at high degree, have resistance to degradation by various intracellular enzymes, high cellular up take, amenable to irreversible cross-linking. Large scale synthesis of these oligonucleotides (upto 10gm) is proposed via solid phase synthesis. The prototype method would be developed on the DNA series, followed by one oligonucleotide in 2'-alkyl series.